PROJECT SUMMARY/ABSTRACT The distinctive effects of combined nicotine and tobacco product (NTP) and cannabis use on neuromaturational brain changes is unknown despite preclinical evidence of a functional interaction between delta-9-tetrahydrocannabinol (THC) and nicotine in the brain that may enhance susceptibility to the development of problematic substance use patterns and addiction severity symptoms. As cannabis becomes more socially accepted and accessible and nicotine delivery methods become more advanced and widespread among emerging adults, the neurobiological effects of co-use of these two substances during young adulthood must be better understood. The primary objective of the proposed prospective research is to recruit a sample of emerging adults (N=200) ages 18-19 at enrollment for three in-person assessments over three years, and a follow-up behavioral interview four years post-enrollment. At enrollment, participants will report either concurrent and simultaneous cannabis and NTP co-use, cannabis use only, NTP use only, and minimal to no use of either substance to compare how cannabis and nicotine use trajectories influence: (1) structural, vascular, and functional brain integrity, (2) neurocognition, (3) stress, emotional distress, and substance use, and (4) circulating endocannabinoid concentrations in blood serum. The study will use cutting-edge neuroimaging techniques (restriction spectrum imaging, pseudo-continuous arterial spin labeling, and high-resolution magnetoencephalography), cognitive testing, bioassays, and detailed mental health assessments at all in- person visits for a more precise understanding of the unique and combined effects of cannabis and NTP use on neural health, behavior, and the endocannabinoid system from ages 18-25 years-old. Young adults are one of our most vulnerable populations (e.g., high peak substance use rates, high vulnerability for addiction, high susceptibility to peer use attitudes and perceptions). As a result, they are specifically targeted by the cannabis and tobacco industry, particularly as the regulatory environment continues to become increasingly permissive for cannabis products. Yet, there is a remarkable paucity of research examining co-use of these two commonly used substances on neural health and neurocognitive functioning in emerging adults. The proposed research will lead to a greater understanding of the unique and combined effects of these substances on protracted brain development and risk for substance use disorders, which will guide neuroscience-informed prevention and intervention programs, public health messages, and public policy.